Inflammatory breast cancer (IBC) is the most lethal form of primary breast cancer and affects African- American women disproportionately. The molecular pathways driving the pathogenesis of IBC remain poorly understood. Therefore, a better understanding of the biology of this cancer is essential for the development of more effective therapies and better detection approaches. Hedgehog (Hh) signaling has been implicated as having a truly central role in the growth of a vast array of cancer types, including breast cancer. Hedgehog signaling has not yet been studied in any detail in IBC. Preliminary data from us and other groups have identified components of the hedgehog pathway as being dysregulated in IBC. This has led to our long-term objective to elucidate the role of hedgehog signaling in inflammatory breast cancer as a prerequisite to the development of new therapies. In this application, we hypothesize that dysregulation of Hh signaling is important for the development and progression of inflammatory breast cancer and that blocking the hedgehog pathway will suppress IBC tumor growth. To test these hypotheses, we propose research with the following specific aims: Aim 1 is to determine the prevalence of expression of Hh and pathway members in IBC cell lines by real-time PCR and immunoblotting and correlate with IBC phenotypic status. Additionally, we will use a gli-luciferase reporter to measure Hh pathway activity in IBC. Aim 2 is to determine the effect of down-regulation of the Hh pathway on IBC cell viability and growth using siRNA against Hh-pathway components or by inhibiting the pathway with small molecule antagonists. The long-term future plan of these studies is to determine if Hh pathway inhibition will attenuate progression of IBC in a mouse model of the disease. Specific aim 3 is to assess the expression of Hedgehog pathway genes in human tumor biopsy samples from inflammatory breast cancer patients and to assess any correlation with tumor and patient characteristics. Inflammatory breast cancer is a devastating disease that progresses at an alarming rate. Our long-term goal is to elucidate the role of hedgehog signaling in inflammatory breast cancer as a prerequisite to the development of new therapies. In summary, in this SC2 pilot proposal, we will characterize hedgehog signaling in IBC. These studies may provide crucial insights into IBC pathogenesis that we anticipate could provide a rational target for future therapy for this fatal disease.